Menorrhagia is over-abundance of the menstrual discharge. Dysmenorrhoea means painful menstruation. Endometriosis is the ectopic implantation and growth of endometrium and can therefore be considered as abnormal growth of cells of the endometrium.
Menorrhagia, dysmenorrhoea and endometriosis affect many women, particularly in the Western world, and represent a significant health problem. At least one in 20 women in the UK aged between 34 and 49 years will consult their general practitioners because of menstrual problems. These women account for more than one in ten of all gynaecological referrals and cost the NHS in excess of £7 million per year for medical prescriptions alone. Perceived abnormal vaginal bleeding is said to account for 70% of the at least 70,000 hysterectomies done each year.
At present, the treatments used for menorrhagia include tranexamic acid or mefenamic acid. In severe cases the treatment is hysterectomy (vaginal or abdominal) but this is a major operation with serious morbidity and some risk of death. A review of treatments for menorrhagia is Stirrat (1999) The Lancet 353, 2175-2176. The development of further and alternative therapies is desirable.
Angiogenesis is of crucial importance in cyclical tissue regeneration and growth in the endometrium and in the development of endometrial disorders including menorrhagia and endometriosis. A major role in the control of endometrial angiogenesis has been established for a number of factors including the VEGF family of genes and their receptors and the fibroblast growth factors (Smith (2001) Trends Endocrinol. Metab. 12[4]: 147-51). However, the mechanisms of angiogenesis in the endometrium remain to be fully elucidated.
The prokineticins, prokineticin 1 (PK1), also known as endocrine-gland-derived vascular endothelial growth factor (EG-VEGF) and prokineticin 2 (PK2), also known as Bv8, are two-recently identified angiogenic factors having 60% sequence identity (LeCouter et al (2001) Nature 412: 877-884; Li et al (2001) Mol. Pharmacol. 59: 692-698; and LeCouter et al (2003) Proc. Natl. Acad. Sci. USA 100: 2685-2690). PK1 mRNA expression has been described in a variety of tissues including steroidogenic glands, namely, ovary, testis and adrenal gland and other tissues including the gastrointestinal tract, nervous system, bladder and prostate (LeCouter et al (2001); Li et al (2001)). PK2 expression shows a similar distribution, but is generally weaker with strongest expression in the testis and peripheral blood leukocytes (Li et al (2001); LeCouter et al (2003)). Analysis by RNA or Northern hybridisation has demonstrated low levels of PK1 and PK2 expression in the human uterus, but with greater expression of PK1 (Li et al (2001)).
The prokineticins are ligands for two closely homologous G protein-coupled receptors, prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2), activation of which leads to calcium mobilisation, stimulation of phosphoinositide turnover and activation of the MAP kinase signalling pathway. Expression of the prokineticin receptors has been identified in a number of tissues including testis, skin, and the central nervous system (Lin et al (2002) J. Biol. Chem. 277[22]: 19276-280; Soga et al (2002) Biochimica et Biophysica Acta 1579: 173-179).
Initial studies examining the functions of PK1 and PK2 have demonstrated that they promote angiogenesis by causing endothelial cell proliferation and chemotaxis in an organ specific manner (LeCouter et al (2001); LeCouter et al (2003)). In addition, there is evidence that they are secreted in response to hypoxia and are involved in the transmission of the circadian rhythm of the suprachiasmatic nucleus (LeCouter et al (2001); Cheng et al (2002) Nature 417: 405-410).
WO 02/00711 (Genentech, Inc.) describes PK1 (referred to as EG-VEGF) and speculates upon its biological role. WO 02/00711 states that EG-VEGF or agonist or antagonists thereof may be useful in treating a number of disease conditions including cancers such as uterine cancer and endometrial carcinoma. It does not disclose or suggest using an antagonist of EG-VEGF to treat other uterine conditions such as menorrhagia, dysmenorrhoea or endometriosis.